2, 4-diamino-5-phenoxypyrimidines



Patented Nov. 3, 1953 UNITED STATES PATENT OFFICE- 2,4-DIAMINO--PHENOXYPYRIMIDINES corporation of New York No Drawing. Application November 15, 1951, Serial No. 256,618

6 Claims.

The present invention relates to compositions having new and unexpected properties in the treatment of malarial infections. More particularly, it has been discovered that certain parasubstituted 2,4-diamino-S-phenoxy-pyrimidines have eifective anti-plasmodial action against Plasmodium gallz'naceum and Plasmodium berghei. This group of derivatives, when tested by oral administration in chicks infected with Plasmodium. gallinaceum, and in mice infected with Plasmodium berghei, were found to rapidly clear the blood of the parasites. Moreover, these derivatives appear to act on the exoerythrocyte forms of the parasites, so that recurrences of the disease are infrequent. An added characteristic of the new group of derivatives is that they are relatively nontoxic and substantially free of side effects. This application is a continuation in part of application Serial No. 74,462, filed February 3, 1949, now abandoned, related to 2,4-diamino-5- aryloxypyrimidines, and a continuation in part of application Serial No. 185,684, filed September 19, 1950, now forfeited.

The antimalarial activity in the series of 2,4- diamino-5-phenoxypyrimidines is found to be considerably enhanced by substitution of the phenolic group in the para position by certain groupings. Thus 2,4-diamino-5-phenoxypyrimi dine is only feebly active as an antimalarial and the p-methylphenoxy derivative is almost inactive, whereas the 5-p chlorophenoxy derivative is approximately as active as quinine and the pphenylphenoxypyrimidine is approximately 3 times as active as quinine. In some instances further substitution in the 6-position of the pyrimidine with an alkyl group markedly enhances the activity against the malarial parasites. Thus 2,4. diamino 5 p chlorophenoxy 6 methylpyrimidine is about 4.5 times as active as quinine against either P. gallznaceum or P. berghei, being in this respect nearly 5 times as active as the corresponding compound with hydrogen in the 6-position.

The compositions of the present invention may be represented as substituted 2,4-diamino-5-psubstituted phenoxypyrimidines of the following formula where R is selected from the group consisting of hydrogen and methyl and Y is selected from the group consisting of the chloro, bromo, nitro, phenyl, benzyl and hydrindenyl radicals.

These substances may be produced by the condensation of a iorinyl phenoxyacetic ester or an a-phenoxy-/3ketoester with guanidine to give a 2-amino-4-hydroxypyrimidine, which is converted to the diaminopyrimidine by chlorination and amination, or by thiation and amination.

The following examples may serve to illustrate the methods used in the preparation of the compounds of the present invention, but are not intended in any way to limit the invention, the scope of which is defined in the claims.

EXAMPLE 1 2,4-diamino-5-1)-chloropheno:rypyrimidine A mixture of g. (0.46 mole) of ethyl-p-chlorophenoxy acetate and 37 g. (0.50 mole) of ethylformate is added slowly to 500 milliliters of dry diethyl ether containing 10.6 g. (0.46 mole) of sodium wire and the resulting mixture allowed to stand overnight at about room temperature. An alcoholic solution of guanidine (prepared by mixing 35 g. of guanidine hydrochloride and an alcoholic solution of sodium ethylate) is added to the solution and the ether removed by evaporation. The reaction mixture is then heated under a reflux condenser for four hours and the 2- amino 4 hydroxy 5 p chlorophenoxypyrimidine precipitated by adding 3 liters of cold water and then acidifying to a pH of about 6.5. The prc-duct is purified by recrystallization from glacial acetic acid. A portion of the product (15 g.) is dissolved in 50 milliliters of phosphoryl chloride and refluxed for about half an hour. The excess phosphoryl chloride is distilled from the product and the reaction mixture chilled in the presence of cracked ice and neutralized to precipitate the 2-amino--chloro-5-p-chlorophenoxypyrimidine which is washed with water and dried under vacuum.

The amination of the product is performed by treating 3 g. of the 2-aminol-chloro5-p-chloro phenoxypyrimidine with milliliters of a saturated ethanolic ammonia solution in a sealed vessel at a temperature of about C. for a period of sixteen hours. The product is evaporated to dryness ona steam bath and taken up in 50 milliliters of water whereupon the desired diamino derivative is precipitated by the addition of excess saturated sodium hydroxide solution. Purification is performed in aqueous medium by the addition of hydrochloric acid followed by precipitation with sodium hydroxide solution, the pure compound recovered having a M. P. of 173-175 C.

EXAMPLE 2 2,4-diamino- 5 -p-chZorophenwy-6 -methylpyrimidine To a solution of ethyl-alpha chloroaceto-- acetate in alcohol is added an equimolar quantity of sodium p chlorophenolate and themixture was The heated under a reflux condenser'for' 2*days. mixture was poured into water atidth'dethyl-p chlorophenoxyacetoacetate was recovered'by extraction with benzene and ether, and after drying was purified by distillation. The resulting ester was condensed with an equimolecular quan' tity of guanidine carbonate in alcoholic solution on the steam bath and the 2-amino-4-hydroxypyrimidine was recovered from dilute aqueous acetic acid; The" z amino--ch'loro derivative was prepared and'aminated as in the previously given examples; The final product melted at 205207 C.

EXAMPLE 3 2,4-cliamin'o-5-p -bromophenoarypyrimidine' Ethyl p -bromophenoxyacetate' was prepared from pj-bromophenoland ethylbromoacetate with sodium ethylate in ethanolic solution,- formylated and condensed with guanidine to give 2-amino 4-hydroxy- 5-p-bromophenoxypyrimidine (M. P. 248-25 The" crude aminohydroxypyrimidine was chlorinated with phosphoryl-chloride and the product aminated in the usual way. The product after two recrystallizations from ethanol formed as white needles, M. P. 202-204".

EXA M PLE I 2,4-diami1ro-6 pJ-beneg Zphenoxy) -pyrimidine -Benz-ylphenoxyacetic acid was obtained by theu'eaction-of pi-benzylphenol and ethyl bromoacetate and-sodium hydroxideinaqueous alcoholic 'soluti'on (1 6). Esterification gave ethyl pbenzylphenoxyacetate; B; P. 218-221" (20 m'mi). The above ester was formylated" usingsodiurii wire in dry ether and theformyl esther was condensed with an alcoholic guanidine'soluti'on (from the hydrochloride). Chlorination and amination of the resultant aminohydroxypyrimidine gave 2,4 diamino-S-(p-benzylphenoxy)-pyrimidine, M. P.' 186-187".

EXAMPLE '5 2,4-diamin0-5- (p-phenylphenoxy) -pyrimidine 45 two hours. Addition of water and extraction with ether gave an ester solution from which ethyl p-phenylphenoxyacetate, identical with the above prepared substance, was isolated by distillation in vacuo in '70 percent yield.

EXANL'PLE 6 2,4-diamino-5-(p-phenylphenoxy) -6-methylpyrimidine Ethyl a-p-pheny1phenoxyacetoacetate was prepared in the following manner: p-Phenylphenol g.) was dissolved in toluene 1 1. and 11.5 g. of 'so'diu'm addedfi The whole was warmed gently untilthe reaction of the sodium was complete (2-hours). After cooling, 82 g. of a-chloroacetoacetidester-were added, the mixture refluxed for 8- hours. The toluene solution was extracted with water, and the toluene (and traces of water) then removed by distillation. To the residue'was added guanidine carbonate (45 g.) and ethanol (200 ml.) and the whole heated under refiuxior 6 hours. The resultant solution was diluted with water and neutralized with acetic acid, giving g; of Z-amino--hydroxy-S-(pphenylphenoxy) 6-methylpyrimidine.

From 15' g. of the aminohydroxypyrimidine there was obtained, by the usual procedures, 4 g. or 2,4-dia-mino-5-(p-phenylphenoxy) -G-methylpyrimidin'e as long needles melting at 328 with decomposition.

EXAMPLE 7 2,4-diu12zino-5-(p-hydrindenylphenory) pyrimidine Ethyl hydrindenyl'phenoxyacetate (B. P. 255- 60 at 17 'mm.) iwas'p'repared from hydrindenyl phenol and ethyl brom'o'acetate in the presence of sodiumethoxi'de. This was formylated with sodiurn'and ethyl formate and treated with an equimolar quantity of'alcoholic guanidine' solution (ffbmguani'dine hydrochloride and sodium ethoxid'e). The'mixture was refluxed for 10 hours, diluted with water and acidified. The aminoliydroxypyriih'idine; recrystallized from aqueo'izs' acetic acid, melted at ZEN-310.

The aminohydroxy compound (20 g.) was refluxed with phosphorus oxychloride (100' ml.) and the resultant chloro compound was aminated in "the usual manner. The 2,4-diamino-5-(p-hydrin'denylphenoxy)-pyrimidine' was purified by solution 'in"'70% acetic acid followed by precipitation bythe'ad'dition ofwater, M. P. 203-'8.

EXALEPLE 8 2,4-di'amino-5-p-nitrophenowy-6-methylpyrimidine F'om ethyl w-chloroacetoacetate and the sodium derivativehf p nitrophenol toluene the ethyl p nitrop he'noxyacetoacetate was obtained inthe'us'ua'l" way; condensed with guanidine carbonatejand 'the' resultant aminohydroxypyri'midinewas converted to 2,4-diamino-5-p-nitrophnoxy-S methylpyrimidineby chlorination and animation. The melting point was 239-239.5.

The same compound was prepared bythe nitra gio'n of 2 ,4 diarhino 5-phenoxy-6methylpyrimi- Since the base is the physiologically active moiety in any non-toxic salt of any compound described herein, the known non-toxic salts of these derivatives are regarded as the equivalent of the uncombined bases described inthe specification and claims herein.

We claim: 2. 2,4 diamino-5-p-ch1orophenoxy-6-methy1- 1. As a. new compound, a 2,4-diamino-5-phepyrimidine. noxypyrimidine of the formula: 3. 2,4-diamino-5-p-pheny1phenoxypyrimidine. NH 4. 2,4 diamino 5-p-nitrophenoxy-6-methy1- N 5 pyrimidine. C 5. 2,4-diamino-5-p-bromophenoxypyrim1dine. N 6. 2,4 diamino-S-(p-phenylphenoxy) -6-methylpyrimidine.

GEORGE H. HITCHINGS. where R is selected from the group consisting of 10 PETER BYROM RUSSELL. hydrogen and methyl and Y is selected from the ELVIRA A. FALCO.

group consisting of chloro, bromo, nitro, phenyl, hydrindenyl, and benzyl radicals. NO references clted' 

1. AS A NEW COMPOUND, A 2,4-DIAMINO-5-PHENOXYPYRIMIDINE OF THE FORMULA: 